We have previously reported that 25 µg/kg of intravenous (i.v.) delta-9-tetrahydrocannabinol (Δ-9-THC) produces marked increases in heart rate, prolongation of left ventricular ejection time corrected for heart rate (LVETc), and a shortening of the pre-ejection period in normal volunteers. Beta-adrenergic blockade partially attenuates these responses. To elucidate further the mechanism of action of Δ-9-THC, we gave 10 normal volunteers 0.1 mg/ kg of i.v. propranolol and 2 mg of i.v. atropine before they received 25 µg/kg of i.v. Δ-9-THC. Systolic time intervals were compared in the denervated subjects before and after Δ-9-THC. Post Δ-9-THC responses were measured at a time approximating peak psychologic high. Mean ± SEM heart rate before and after Δ-9-THC was 89 ±4 and 87 ± 3 beats/min (NS); mean ± SEM pre-ejection period before and after Δ-9-THC was 107 ± 5 and 109 ± 4 ms (NS); and mean ± SEM LVETC before and after Δ-9-THC was 433 ±6 and 429 ± 6 ms (NS). Since previous denervation of our subjects with atropine and propranaolol totally abolished changes in heart rate and systolic time intervals, the cardiac effects of Δ-9-THC appear to be mediated totally via the autonomic nervous system, probably reflecting direct central nervous system stimulation.